EP3261582A1 - Procédés et compositions relatifs à des antagonistes de la leptine - Google Patents

Procédés et compositions relatifs à des antagonistes de la leptine

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Publication number
EP3261582A1
EP3261582A1 EP15883064.6A EP15883064A EP3261582A1 EP 3261582 A1 EP3261582 A1 EP 3261582A1 EP 15883064 A EP15883064 A EP 15883064A EP 3261582 A1 EP3261582 A1 EP 3261582A1
Authority
EP
European Patent Office
Prior art keywords
composition
leptin
leptin antagonist
tissue
antagonist
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP15883064.6A
Other languages
German (de)
English (en)
Other versions
EP3261582B1 (fr
EP3261582A4 (fr
Inventor
Jacob Schneiderman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Remodeless Cv Ltd
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US14/730,282 external-priority patent/US10105469B2/en
Application filed by Individual filed Critical Individual
Publication of EP3261582A1 publication Critical patent/EP3261582A1/fr
Publication of EP3261582A4 publication Critical patent/EP3261582A4/fr
Application granted granted Critical
Publication of EP3261582B1 publication Critical patent/EP3261582B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2264—Obesity-gene products, e.g. leptin
    • A—HUMAN NECESSITIES
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
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    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/047—Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43—Hormones, e.g. dexamethasone
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/436—Inhibitors, antagonists of receptors
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    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves

Definitions

  • the present invention relates to the field of medicine, and in some embodiments to compositions comprising a leptin antagonist formulated for localized release of a leptin antagonist at the site of treatment as well as methods of using such compositions for treating disorders, including cardiovascular disorders.
  • Cardiovascular disease is a class of diseases that involve the heart and or the blood vessels.
  • CVD cardiovascular disease
  • CRP C-reactive protein
  • osteoprotegerin which is involved with regulation of NF-KB, has been found to be a risk factor for cardiovascular disease and mortality [Venuraju et al., 2010 J. Am. Coll. Cardiol. 55 (19): 2049-61].
  • cardiovascular disorders can benefit from suppression of inflammation-related processes and cellular proliferation as part of a remodeling response (e.g. use of locally released cytotoxic drugs such as paclitaxel or sirolimus in preventing restenosis or use of doxycycline in treatment of abdominal aortic aneurysm (AAA)), to date, there is no evidence to suggest that cardiovascular disease can benefit from anti-inflammatory treatment.
  • cytotoxic drugs such as paclitaxel or sirolimus in preventing restenosis or use of doxycycline in treatment of abdominal aortic aneurysm (AAA)
  • Leptin is a naturally occurring pleiotropic molecule that regulates food intake as well as metabolic and endocrine functions. Leptin also plays a regulatory role in immunity, inflammation, and hematopoiesis.
  • the human leptin precursor is a linear polypeptide 167 amino acid residues long represented by NCBI Reference Sequence NP_000221.1 encoded by the mRNA having the nucleotide sequence NCBI Reference Sequence NM_000230. Residues 1-21 of the sequence constitute the signal peptide while residues 22-167 constitute the mature hormone.
  • Leptin antagonists are also known, see for example, US 7,307,142 and US 8,969,292.
  • the invention in some embodiments, relates to the field of medicine, and more particularly to methods and devices that use leptin antagonists.
  • the invention relates to compositions comprising a leptin antagonist formulated for localized release of a leptin antagonist at the site of treatment as well as methods of using such compositions for treating disorders, including cardiovascular disorders.
  • a method of treatment comprising: exposing in vivo tissue of a subject in need thereof to local administration of a pharmaceutically-effective amount of leptin antagonist, thereby providing a therapeutic effect to the tissue.
  • the tissue is substantially continuously exposed to a pharmaceutically-effective amount of leptin antagonist for a period of not less than three days, not less than 5 days, not less than 8 days and even not less than 14 days.
  • a method of treatment comprising implanting in contact with tissue in the body of a subject in need thereof a composition configured for in vivo local administration of leptin antagonist, thereby providing a therapeutic effect to the tissue.
  • the configuration for the in vivo release is such that when the composition is implanted in vivo, leptin antagonist is released from the composition in a pharmaceutically-effective amount for a period of not less than three days, not less than 5 days, not less than 8 days and even not less than 14 days.
  • the need is that the subject suffers from at least one pathology selected from the group consisting of: cardiovascular disease; remodeling of stable athersclerotic plaque into an unstable lesion; ascending aortic aneurysm-associated hypertension, hypercholesterolemia or diabetes mellitus; bicuspid aortic valve; Takayasu disease; rheumatoid arteritis; Marfan's syndrome; ankylosing spondylitis; giant cell arteritis; inflammatory aortic aneurysm; pulmonary artery aneurysm in Marfan's syndrome; aortic dissection in an aortic or peripheral large artery; angiogenesis; cancer; local discrete lesion therapy; and arteriovenous malformation.
  • cardiovascular disease remodeling of stable athersclerotic plaque into an unstable lesion
  • bicuspid aortic valve Takayasu disease
  • the need is that the subject suffers from a cardiovascular disorder, wherein the therapeutic effect is down-regulation of an expression or activity of leptin in a cardiovascular tissue.
  • the cardiovascular tissue is aortic and/or mitral heart valve leaflet tissue.
  • the local administration is effected by positioning a carrier capable of releasing the leptin antagonist on an outer wall (e.g., tunica externa) or the inner wall (e.g., tunica intima) of an aorta.
  • the cardiovascular tissue is arterial or venous wall tissue.
  • the local administration is effected by positioning a carrier capable of releasing the leptin antagonist on an outer wall (e.g., tunica externa) or the inner wall (e.g., tunica intima) of the arterial or venous wall tissue.
  • the cardiovascular disorder is a vascular aneurysm. In some embodiments, the cardiovascular disorder is an aortic vascular disorder. In some embodiments, the cardiovascular disorder is left ventricular remodeling.
  • the local administration is effected via an intravascular catheter. In some embodiments, the local administration is effected via direct injection.
  • a method for treatment of athersclerotic plaque comprising: administering a pharmaceutically-effective amount of a leptin antagonist to athersclerotic plaque accumulated in the inner walls of an artery, thereby at least one of: (a) reducing the rate and (b) reducing the incidence, of conversion of a stable athersclerotic plaque to an unstable lesion.
  • composition comprising a leptin antagonist and a carrier, for use in treating a disorder selected from the group consisting of: cardiovascular disease; remodeling of stable athersclerotic plaque into an unstable lesion; ascending aortic aneurysm-associated hypertension, hypercholesterolemia or diabetes mellitus; bicuspid aortic valve; Takayasu disease; rheumatoid arteritis; Marfan's syndrome; ankylosing spondylitis; giant cell arteritis; inflammatory aortic aneurysm; pulmonary artery aneurysm in Marfan's syndrome; aortic dissection in an aortic or peripheral large artery; site of arterial anastomosis, angiogenesis; cancer; local neoplastic discrete lesion therapy; and arteriovenous malformation, wherein the carrier is configured for localized administration of the leptin antagonist.
  • the carrier is a biodegradable support.
  • the biodegradable support is composed of a polymer selected from the group consisting of a hydrogel, poly glycolic acid (PGA), poly lactic co-glycolic acid (PLGA), polylactide (PLA), and poly (L-lactide) (PLLA), and combinations thereof.
  • the carrier is a hydrogel. In some embodiments, the carrier is configured as a film. In some embodiments, the carrier is a device selected from the group consisting of a mesh, a balloon and a vascular graft. In some embodiments, the carrier is a depot-forming injectable composition.
  • the disorder is a cardiovascular disorder, wherein the leptin antagonist effects down-regulation of an expression or activity of leptin in a cardiovascular tissue.
  • the cardiovascular disorder is a vascular disorder.
  • the vascular disorder is an aortic vascular disorder.
  • the cardiovascular disorder is left ventricular remodeling.
  • the cardiovascular tissue is aortic and/or mitral heart valve leaflet tissue. In some such embodiments, the cardiovascular tissue is arterial or venous wall tissue.
  • the local administration is effected by positioning a carrier capable of releasing the leptin antagonist on a location selected from the group consisting of: an outer wall of an aorta, an outer wall of an artery, an outer wall of an vein, a luminal surface of an aorta, a luminal surface of an artery and a luminal surface of an vein.
  • the local administration is effected by positioning a carrier capable of releasing the leptin antagonist on an outer wall (e.g., tunica externa) or the inner wall (e.g., tunica intima) of the arterial or venous wall tissue.
  • the localized administration is to be effected via an intravascular catheter. In some embodiments, the localized administration is to be effected via direct injection.
  • a method of treating a condition in a subject in need thereof comprising administering intracavitarily to inner walls of a fluid-filled bodily cavity of the subject a composition comprising a leptin antagonist.
  • a composition comprising: a leptin antagonist for use in treating a condition, wherein the composition is configured for intracavitary administration to inner walls of a fluid-filled bodily cavity of a subject.
  • an intracavitarily-implantable medical device comprising: at least one solid functional device part configured for deploying the device in a fluid-filled bodily cavity of a subject; and functionally associated with at least one the device component, a leptin antagonist.
  • a surgical connecting device comprising: a solid device body made of a material; and functionally associated with the device body, a pharmaceutically-effective amount of leptin antagonist.
  • the device body is in the form selected from the group consisting of surgical suture thread and a surgical staple.
  • any suitable leptin antagonist may be used for implementing the teachings herein.
  • Various types and specific suitable leptin antagonists are listed in the description herein.
  • the leptin antagonist is capable of binding a leptin receptor.
  • the leptin antagonist is incapable of dimerization.
  • the leptin antagonist comprises a polypeptide portion.
  • the leptin antagonist is selected from the group consisting of a polypeptide, a salt, and/or an ester thereof.
  • the leptin antagonist is a modified leptin polypeptide.
  • FIG. la-c illustrate a gel ( Figure la), film ( Figure lb) and mesh ( Figure lc) for local release of a leptin antagonist.
  • FIG. 2 illustrates a balloon catheter configured for local release of a leptin antagonist(drug release indicated by arrows).
  • FIG. 3 illustrates a slow release leptin eluted from a scaffold.
  • FIG. 4 illustrates the location of leptin film application on the anterior outer surface of the ascending aorta.
  • Human arch angiogram depicts mouse anatomy.
  • FIG. 5 illustrates a time course analysis of serum leptin level in ApoE "A mice that underwent peri-aortic application of leptin film (20 ⁇ g).
  • FIG. 6 illustrates increased ascending aortic diameter at the location of leptin film application versus controls.
  • FIG. 7 illustrates elastica staining and aSMA IHC analysis of ascending aortic cross sections of mice locally treated with leptin versus controls.
  • FIG. 8 illustrates change in left ventricle (LV) wall thickness in leptin-treated (filled columns) versus control (open columns) mice.
  • FIG. 9 illustrates LV diameter in systole and diastole in leptin-treated (filled columns) and control (open columns) mice.
  • FIG. 10 illustrates LV fractional area change in leptin-treated (filled columns) versus control (open columns) mice.
  • FIG. 11 illustrates aortic and mitral valve leaflet thickness in leptin-treated and control mice.
  • FIG. 12 illustrates mean systolic blood pressure in angiotensin II treated mice.
  • FIG. 13 illustrates a time course analysis presenting weight of angiotensin II treated mice (open triangles), and mice receiving both, angiotensin II and leptin antagonist (LA).
  • FIG. 14 illustrates number of mice that succumbed due to ruptured abdominal and thoracic aneurysms in angiotensin II treated mice versus mice receiving angiotensin II and leptin antagonist (LA).
  • FIG. 15 illustrates ascending aortic dilatation in angiotensin II treated mice versus mice receiving angiotensin II and leptin antagonist (LA).
  • FIG. 16 illustrates elastic lamella fragmentation and aSMA depletion in angiotensin II treated mice versus mice receiving angiotensin II and leptin antagonist (LA).
  • FIG. 17 illustrates leptin expression in medial SMCs (arrows) and macrophages of atherosclerotic lesions (filled arrowheads) in angiotensin II treated, angiotensin II and leptin antagonist (LA) treated, and control mice.
  • FIG. 18 illustrates LV hypertrophy in angiotensin II treated mice versus mice receiving angiotensin II and leptin antagonist (LA).
  • FIG. 19 illustrates changes in LV diameter in angiotensin II treated mice versus mice receiving angiotensin II and leptin antagonist (LA).
  • FIG. 20 illustrates LV fractional area change in angiotensin II treated mice (open column) versus mice receiving angiotensin II and leptin antagonist (LA) (filled column).
  • FIG. 21 illustrates peak systolic velocity at the aortic valve in angiotensin II treated mice versus mice receiving angiotensin II and leptin antagonist (LA).
  • FIG. 22 illustrates aortic and mitral valve thickness (graph on left), and staining of valve leaflets with H&E (panels F-I).
  • aSMA and TGFp panels J-M', staining for aortic valves
  • LA leptin antagonist
  • FIG. 23 illustrates expression of leptin (D), and leptin receptor (E) in normal human aortic valve leaflet tissue.
  • FIG. 24 illustrates leptin and leptin receptor antigen prevalent in severe aortic valve stenosis, evident in SMC-like cells, and infiltrating macrophages.
  • FIG. 25 illustrates leptin and leptin receptor mRNA levels in leaflets of stenosed aortic valve versus normal aortic valve controls, and fat tissue (as positive control);
  • FIG. 26 illustrates proliferation of valve interstitial cells (VICs) in response to leptin stimulation.
  • FIG. 27 schematically depicts embodiments of surgical connecting devices according to the teachings herein;
  • FIG. 28 schematically depicts embodiments of the teachings herein suitable for intracavitary administration of leptin antagonist.
  • FIG. 29 schematically depicts further embodiments of the teachings herein suitable for intracavitary administration of leptin antagonist.
  • the invention in some embodiments, relates to the field of medicine, and more particularly to methods and devices that use leptin antagonists.
  • the invention relates to compositions comprising a leptin antagonist formulated for localized release of a leptin antagonist at the site of treatment as well as methods of using such compositions for treating disorders, including cardiovascular disorders.
  • the compositions comprising a leptin antagonist can be used for localized suppression of leptin-related conditions, including tissue remodeling processes.
  • leptin might play a role in vascular inflammation, oxidative stress, and vascular smooth muscle hypertrophy that may contribute to coronary heart disease among other pathologies
  • leptin activity can be used to treat cardiovascular disorders characterized by remodeling of cardiovascular tissue such as cardiac, arterial or valve tissue.
  • the present inventor set out to elucidate the role of leptin in disorders, such as cardiovascular disorders by employing a leptin antagonist in a localized manner.
  • the present inventor has discovered an unexpected pharmaceutical efficacy of locally administered leptin antagonists, especially leptin antagonists administered by sustained release.
  • the present inventor has found that in vivo implantation of a composition configured for sustained-release of leptin antagonist can have a desirable pharmaceutical effect on tissue in proximity of the implanted composition with limited or no substantial side- effects, for example, no discernible hormonal or immunological effects.
  • leptin antagonist from the composition has not been found to be washed away by the fluid and, instead, has been found to interact with the tissue providing a desirable pharmaceutical effect.
  • leptin antagonist released from the composition passes into and through the cavity walls (e.g., tunica intima) in pharmaceutically-effective amounts.
  • the intima of healthy cardiovascular intima is relatively impermeable to leptin antagonist released from the composition, so that there is little or no passage of leptin antagonist into and through the endothelium and underlying tissue, thereby avoiding substantial negative side-effects.
  • the permeability of the cardiovascular intima during inflammation increases sufficiently to allow passage of a therapeutically-effective amount of leptin antagonist released from the composition into the tissue. It is currently believed that this effect is self-regulating.
  • a higher degree of inflammation leads to a higher degree of intima permeability allowing passage of more leptin antagonist leading to a relatively high dose of leptin antagonist in the more pathological tissue.
  • intima permeability decreases thereby decreasing the dose of leptin antagonist actually in the tissue that is still sufficient to exercise a desired pharmaceutical effect but with a reduced incidence of substantial negative side effects.
  • the present invention includes local administration of leptin antagonist to treat and attenuate expansion of ascending aortic aneurysm, and corresponding cardiac sequelae (driven by the aorto-ventricular coupling), including left ventricular hypertrophy, as well as hyperplasia of left heart valve leaflets.
  • the present invention includes treatment of peripheral vascular disorders such as the progression of arterial or venous aneurysms while minimizing systemic exposure to the administered leptin antagonist.
  • a composition comprising a leptin antagonist and a carrier configured for localized administration, for treating disorders such as cardiovascular disorders.
  • cardiovascular disorders refer to disorders of the cardiovascular system, i.e. the heart and central, cranial and peripheral vasculature. Examples of such disorders include, but are not limited to valve stenosis, aneurysms, vessel response to vascular injury, cardiomyopathy and the like.
  • the carrier can be a solid, gel or liquid carrier
  • the leptin antagonist can be any agent capable of down-regulating leptin activity in the target tissue.
  • a leptin antagonist include agents capable of binding and/or degrading leptin or leptin receptors as well as agents capable of down-regulating leptin expression (at the DNA or RNA levels, i.e., agents capable of blocking transcription or translation). Specific preferred leptin antagonists are listed hereinbelow.
  • a leptin antagonist that is an agent capable of down-regulating leptin is an antibody or antibody fragment capable of specifically binding leptin or a leptin receptor.
  • the antibody specifically binds at least one epitope of leptin, e.g., an epitope defined amino acids 26-59 of mammalian leptin (e.g. rat leptin).
  • epitope refers to any antigenic determinant on an antigen to which the paratope of an antibody binds.
  • antibody refers to a substantially intact antibody molecule.
  • antibody fragment refers to a functional fragment of an antibody that is capable of binding to an antigen.
  • Suitable antibody fragments for practicing the present invention include, inter alia, a complementarity-determining region (CDR) of an immunoglobulin light chain (referred to herein as “light chain”), a CDR of an immunoglobulin heavy chain (referred to herein as “heavy chain”), a variable region of a light chain, a variable region of a heavy chain, a light chain, a heavy chain, an Fd fragment, and antibody fragments comprising essentially whole variable regions of both light and heavy chains such as an Fv, a single-chain Fv, an Fab, an Fab', and an F(ab')2.
  • Fv defined as a genetically engineered fragment consisting of the variable region of the light chain and the variable region of the heavy chain expressed as two chains;
  • scFv single-chain Fv
  • Fab a fragment of an antibody molecule containing a monovalent antigen- binding portion of an antibody molecule, obtained by treating whole antibody with the enzyme papain to yield the intact light chain and the Fd fragment of the heavy chain, which consists of the variable and CHI domains thereof;
  • Fab' a fragment of an antibody molecule containing a monovalent antigen- binding portion of an antibody molecule, obtained by treating whole antibody with the enzyme pepsin, followed by reduction (two Fab' fragments are obtained per antibody molecule);
  • F(ab')2 a fragment of an antibody molecule containing a monovalent antigen- binding portion of an antibody molecule, obtained by treating whole antibody with the enzyme pepsin (i.e., a dimer of Fab' fragments held together by two disulfide bonds).
  • Antibodies may be generated via any one of several known methods, which may employ induction of in vivo production of antibody molecules, screening of immunoglobulin libraries (Orlandi, R. et al. (1989). Cloning immunoglobulin variable domains for expression by the polymerase chain reaction. Proc Natl Acad Sci USA 86, 3833-3837; and Winter, G. and Milstein, C. (1991). Man-made antibodies. Nature 349, 293-299), or generation of monoclonal antibody molecules by continuous cell lines in culture.
  • haptens can be coupled to antigenically neutral carriers such as keyhole limpet hemocyanin (KLH) or serum albumin (e.g., bovine serum albumin (BSA)) carriers (see, for example, US. Pat. Nos. 5,189,178 and 5,239,078).
  • KLH keyhole limpet hemocyanin
  • BSA bovine serum albumin
  • Coupling a hapten to a carrier can be effected using methods well known in the art. For example, direct coupling to amino groups can be effected and optionally followed by reduction of the imino linkage formed.
  • the carrier can be coupled using condensing agents such as dicyclohexyl carbodiimide or other carbodiimide dehydrating agents.
  • Condensing agents such as dicyclohexyl carbodiimide or other carbodiimide dehydrating agents.
  • Linker compounds can also be used to effect the coupling; both homobifunctional and heterobifunctional linkers are available from Pierce Chemical Company, Rockford, Illinois, USA.
  • the resulting immunogenic complex can then be injected into suitable mammalian subjects such as mice, rabbits, and others. Suitable protocols involve repeated injection of the immunogen in the presence of adjuvants according to a schedule designed to boost production of antibodies in the serum.
  • the titers of the immune serum can readily be measured using immunoassay procedures which are well known in the art.
  • the antisera obtained can be used directly or monoclonal antibodies may be obtained, as described hereinabove.
  • Antibody fragments may be obtained using methods well known in the art. (See, for example, Harlow, E. and Lane, D. (1988). Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, New York.)
  • antibody fragments according to the present invention can be prepared by proteolytic hydrolysis of the antibody or by expression in E. coli or mammalian cells (e.g., Chinese hamster ovary (CHO) cell culture or other protein expression systems) of DNA encoding the fragment.
  • E. coli or mammalian cells e.g., Chinese hamster ovary (CHO) cell culture or other protein expression systems
  • antibody fragments can be obtained by pepsin or papain digestion of whole antibodies by conventional methods.
  • an (Fab') 2 antibody fragments can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment. This fragment can be further cleaved using a thiol reducing agent, and optionally a blocking group for the sulfhydryl groups resulting from cleavage of disulfide linkages, to produce 3.5S Fab' monovalent fragments.
  • enzymatic cleavage using pepsin produces two monovalent Fab' fragments and an Fc fragment directly.
  • Ample guidance for practicing such methods is provided in the literature of the art (for example, refer to: U.S.
  • an Fv is composed of paired heavy chain variable and light chain variable domains. This association may be noncovalent (see, for example, Inbar, D. et al. (1972). Localization of antibody-combining sites within the variable portions of heavy and light chains. Proc Natl Acad Sci USA 69, 2659-2662). Alternatively, as described hereinabove, the variable domains may be linked to generate a single-chain Fv by an intermolecular disulfide bond, or alternately such chains may be cross-linked by chemicals such as glutaraldehyde.
  • the Fv is a single-chain Fv.
  • Single-chain Fvs are prepared by constructing a structural gene comprising DNA sequences encoding the heavy chain variable and light chain variable domains connected by an oligonucleotide encoding a peptide linker. The structural gene is inserted into an expression vector, which is subsequently introduced into a host cell such as E. coli. The recombinant host cells synthesize a single polypeptide chain with a linker peptide bridging the two variable domains.
  • Ample guidance for producing single-chain Fvs is provided in the literature of the art (see, e.g.: Whitlow, M. and Filpula, D. (1991). Single-chain Fv proteins and their fusion proteins.
  • Isolated complementarity-determining region peptides can be obtained by constructing genes encoding the CDR of an antibody of interest. Such genes may be prepared, for example, by RT-PCR of the mRNA of an antibody-producing cell. Ample guidance for practicing such methods is provided in the literature of the art (e.g., Larrick, J. W. and Fry, K. E. (1991). PCR Amplification of Antibody Genes. METHODS: A Companion to Methods in Enzymology 2(2), 106- 110).
  • humanized antibodies are preferred.
  • Humanized forms of non-human (e.g., murine) antibodies are genetically engineered chimeric antibodies or antibody fragments having (preferably minimal) portions derived from non-human antibodies.
  • Humanized antibodies include antibodies in which the CDRs of a human antibody (recipient antibody) are replaced by residues from a CDR of a non-human species (donor antibody), such as mouse, rat, or rabbit, having the desired functionality.
  • donor antibody such as mouse, rat, or rabbit
  • the Fv framework residues of the human antibody are replaced by corresponding non-human residues.
  • Humanized antibodies may also comprise residues found neither in the recipient antibody nor in the imported CDR or framework sequences.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-human antibody and all or substantially all of the framework regions correspond to those of a relevant human consensus sequence.
  • Humanized antibodies optimally also include at least a portion of an antibody constant region, such as an Fc region, typically derived from a human antibody (see, for example: Jones, P. T. et al. (1986). Replacing the complementarity- determining regions in a human antibody with those from a mouse. Nature 321, 522-525; Riechmann, L. et al. (1988). Reshaping human antibodies for therapy. Nature 332, 323-327; Presta, L. G. (1992b). Curr Opin Struct Biol 2, 593-596; and Presta, L. G. (1992a). Antibody engineering. Curr Opin Biotechnol 3(4), 394-398).
  • a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as imported residues, which are typically taken from an imported variable domain. Humanization can be performed essentially as described (see, for example: Jones et al. (1986); Riechmann et al. (1988); Verhoeyen, M. et al. (1988). Reshaping human antibodies: grafting an antilysozyme activity. Science 239, 1534-1536; and U.S. Pat. No. 4,816,567), by substituting human CDRs with corresponding rodent CDRs.
  • humanized antibodies are chimeric antibodies, wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species.
  • humanized antibodies may be typically human antibodies in which some CDR residues and possibly some framework residues are substituted by residues from analogous sites in rodent antibodies.
  • Human antibodies can also be produced using various additional techniques known in the art, including phage-display libraries (Hoogenboom, H. R. and Winter, G. (1991). Bypassing immunization. Human antibodies from synthetic repertoires of germline VH gene segments rearranged in vitro. J Mol Biol 227, 381-388; Marks, J. D. et al. (1991). By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J Mol Biol 222, 581-597; Cole et al. (1985), Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96; and Boerner, P. et al. (1991).
  • Humanized antibodies can also be created by introducing sequences encoding human immunoglobulin loci into transgenic animals, e.g., into mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon antigenic challenge, human antibody production is observed in such animals which closely resembles that seen in humans in all respects, including gene rearrangement, chain assembly, and antibody repertoire. Ample guidance for practicing such an approach is provided in the literature of the art (for example, refer to: U.S. Pat. Nos.
  • antibodies After antibodies have been obtained, they may be tested for activity, for example via enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • Anti-leptin antibodies as well as epitope sequences suitable for generating antibodies and antibody fragments are described in US20070104708 which is incorporated herein by reference as if fully set-forth herein.
  • Leptin peptide antagonists can also be used with the present invention.
  • leptin antagonist a modified mammalian leptin polypeptide termed superactive leptin mutein is disclosed in US20130133089 which is incorporated by reference as if fully set-forth herein.
  • peptide encompass native peptides (either degradation products, synthetically synthesized peptides, or recombinant peptides), peptidomimetics (typically, synthetically synthesized peptides), and the peptide analogues peptoids and semipeptoids, and may have, for example, modifications rendering the peptides more stable while in a body or more capable of penetrating into cells.
  • Methods for preparing peptidomimetic compounds are well known in the art and are specified, for example, in Ramsden, C. A., ed. (1992), Quantitative Drug Design, Chapter 17.2, F. Choplin Pergamon Press, which is incorporated by reference as if fully set forth herein. Further details in this respect are provided hereinbelow.
  • Natural aromatic amino acids, Trp, Tyr, and Phe may be substituted for synthetic non-natural acids such as, for instance, tetrahydroisoquinoline-3-carboxylic acid (TIC), naphthylelanine (Nol), ring-methylated derivatives of Phe, halogenated derivatives of Phe, and o-methyl-Tyr.
  • TIC tetrahydroisoquinoline-3-carboxylic acid
  • Nol naphthylelanine
  • ring-methylated derivatives of Phe ring-methylated derivatives of Phe
  • halogenated derivatives of Phe halogenated derivatives of Phe
  • o-methyl-Tyr o-methyl-Tyr
  • the peptides of the present invention may also include one or more modified amino acids or one or more non-amino acid monomers (e.g., fatty acids, complex carbohydrates, etc.).
  • modified amino acids e.g., fatty acids, complex carbohydrates, etc.
  • amino acid or “amino acids” is understood to include the 20 naturally occurring amino acids; those amino acids often modified post-translationally in vivo, including, for example, hydroxyproline, phosphoserine, and phosphothreonine; and other less common amino acids, including but not limited to 2-aminoadipic acid, hydroxylysine, isodesmosine, nor-valine, nor-leucine, and ornithine.
  • amino acid includes both D- and L-amino acids.
  • Amino acids are referred to by the standard three letter code. Amino acids are L amino acids unless otherwise noted, for example, by addition of the prefix "D".
  • the code Trp refers to L-tryptophan, while the codes D-Trp and DTrp refers to D-tryptophan.
  • the code Aib refers to 2-aminoisobutyric acid.
  • the code Orn refers to ornithine.
  • Lys-Ac refers to acetyllysine.
  • HomoLys refers to homolysine.
  • H-Cys refers to homocysteine.
  • peptidic leptin antagonists used to implement the teachings herein are utilized in a linear form, although in some embodiments, cyclic forms thereof are used.
  • peptidic leptin antagonists used to implement the teachings herein are synthesized by any techniques that are known to those skilled in the art of peptide synthesis.
  • solid phase peptide synthesis a summary of the many techniques may be found in: Stewart, J. M. and Young, J. D. (1963), “Solid Phase Peptide Synthesis,” W. H. Freeman Co. (San Francisco); and Meienhofer, J (1973). "Hormonal Proteins and Peptides,” vol. 2, p. 46, Academic Press (New York).
  • peptide synthesis methods comprise the sequential addition of one or more amino acids or suitably protected amino acids to a growing peptide chain.
  • amino acids or suitably protected amino acids Normally, either the amino or the carboxyl group of the first amino acid is protected by a suitable protecting group.
  • the protected or derivatized amino acid can then either be attached to an inert solid support or utilized in solution by adding the next amino acid in the sequence having the complimentary (amino or carboxyl) group suitably protected, under conditions suitable for forming the amide linkage.
  • the protecting group is then removed from this newly added amino acid residue and the next amino acid (suitably protected) is then added, and so forth; traditionally this process is accompanied by wash steps as well.
  • any remaining protecting groups are removed sequentially or concurrently, to afford the final peptide compound.
  • this general procedure it is possible to add more than one amino acid at a time to a growing chain, for example, by coupling (under conditions which do not racemize chiral centers) a protected tripeptide with a properly protected dipeptide to form, after deprotection, a pentapeptide, and so forth.
  • a preferred method of preparing the peptide compounds of the present invention involves solid- phase peptide synthesis, utilizing a solid support.
  • peptidic leptin antagonists used to implement the teachings herein are generated using cell expression approaches by utilizing expression vectors for prokaryotic or eukaryotic expression or alternatively, the peptide can be expressed in-situ by delivering a suitable expression construct to cardiovascular tissue.
  • a polynucleotide sequence encoding the peptide is preferably ligated into a nucleic acid construct suitable for mammalian cell expression.
  • a nucleic acid construct suitable for mammalian cell expression.
  • Such a nucleic acid construct includes a promoter sequence for directing transcription of the polynucleotide sequence in the cell in a constitutive or inducible manner.
  • Constitutive promoters suitable for use with the present invention are promoter sequences that are active under most environmental conditions and most types of cells, such as the cytomegalovirus (CMV) and Rous sarcoma virus (RSV).
  • CMV cytomegalovirus
  • RSV Rous sarcoma virus
  • Polyadenylation sequences can also be added to the expression vector in order to increase the efficiency of mRNA translation.
  • Two distinct sequence elements are required for accurate and efficient polyadenylation: GU- or U-rich sequences located downstream from the polyadenylation site and a highly conserved sequence of six nucleotides, namely AAUAAA, located 11-30 nucleotides upstream of the site.
  • Termination and polyadenylation signals suitable for the present invention include those derived from SV40.
  • the expression vector of the present invention may typically contain other specialized elements intended to increase the level of expression of cloned nucleic acids or to facilitate the identification of cells that carry the recombinant DNA.
  • a number of animal viruses contain DNA sequences that promote extra-chromosomal replication of the viral genome in permissive cell types. Plasmids bearing these viral replicons are replicated episomally as long as the appropriate factors are provided by genes either carried on the plasmid or with the genome of the host cell.
  • the expression vector of the present invention may or may not include a eukaryotic replicon. If a eukaryotic replicon is present, the vector is capable of amplification in eukaryotic cells using the appropriate selectable marker. If the vector does not comprise a eukaryotic replicon, no episomal amplification is possible.
  • mammalian expression vectors include, but are not limited to, pcDNA3, pcDNA3.1 (+/-), pGL3, pZeoSV2(+/-), pSecTag2, pDisplay, pEF/myc/cyto, pCMV/myc/cyto, pCR3.1, pSinRep5, DH26S, DHBB, pNMTl, pNMT41, and pNMT81, which are available from Invitrogen, pCI which is available from Promega, pMbac, pPbac, pBR-RSV and pBK- CMV, which are available from Strategene, pTRES which is available from Clontech, and their derivatives.
  • Expression vectors containing regulatory elements from eukaryotic viruses such as retroviruses can be also used.
  • SV40 vectors include pSVT7 and pMT2, for instance.
  • Vectors derived from bovine papilloma virus include pBV-lMTHA, and vectors derived from Epstein-Barr virus include pHEBO and p205.
  • exemplary vectors include pMSG, pAV009/A + , pMTO10/A + , pMAMneo-5, baculovirus pDSVE, and any other vector allowing expression of proteins under the direction of the SV40 early promoter, SV40 later promoter, metallothionein promoter, murine mammary tumor virus promoter, Rous sarcoma virus promoter, polyhedrin promoter, or other promoters shown effective for expression in eukaryotic cells.
  • Viruses are very specialized infectious agents that have evolved, in many cases, to elude host defense mechanisms. Typically, viruses infect and propagate in specific cell types.
  • the targeting specificity of viral vectors utilizes its natural specificity to specifically target predetermined cell types and thereby introduce a recombinant gene into the infected cell.
  • the type of vector used by the present invention will depend on the cell type transformed. The ability to select suitable vectors according to the cell type transformed is well within the capabilities of the ordinarily skilled artisan and as such, no general description of selection considerations is provided herein.
  • bone marrow cells can be targeted using the human T-cell leukemia virus type I (HTLV-I) and kidney cells may be targeted using the heterologous promoter present in the baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV), as described by Liang, C. Y. et al. (2004). High efficiency gene transfer into mammalian kidney cells using baculovirus vectors. Arch Virol 149, 51-60.
  • HTLV-I human T-cell leukemia virus type I
  • AcMNPV baculovirus Autographa californica multiple nucleopolyhedrovirus
  • Recombinant viral vectors are useful for in vivo expression of a leptin peptide since they offer advantages such as lateral infection and targeting specificity.
  • Lateral infection is inherent in the life cycle of retrovirus, for example, and is the process by which a single infected cell produces many progeny virions that bud off and infect neighboring cells. The result is the rapid infection of a large area of cells, most of which were not initially infected by the original viral particles. This is in contrast to vertical-type infection in which the infectious agent spreads only through daughter progeny.
  • Viral vectors can also be produced that are unable to spread laterally. This characteristic can be useful if the desired purpose is to introduce a specified gene into only a localized number of targeted cells.
  • compositions also called, compositions-of-matter
  • a carrier for local delivery of the leptin antagonist can be a mesh (Figure lc) an injectable gel (e.g. in-situ forming depot) ( Figures la), a thin (preferably biodegradable) film (Figure lb), a scaffold ( Figure 3).
  • the composition is a coating on a medical device ( Figure 27 A).
  • a medical device is impregnated with the composition (Figure 27B).
  • the composition is in the form of a sheet (such as the film of Figure lb or the mesh of Figure lc) that constitutes a portion of a medical device such as a stent cover (Figure 27C) or graft of a graft-stent assembly (Figure 27D).
  • a medical device such as a stent cover ( Figure 27C) or graft of a graft-stent assembly ( Figure 27D).
  • the composition constitutes a medical device (Figure 27E).
  • a carrier of a composition is a balloon catheter, or a composition is delivered locally using a drug-eluting balloon catheter ( Figure 2).
  • Figure 2 The manufacture and use of drug-eluting balloons for localized delivery of active-pharmaceutical ingredients are well known in the art (especially to the walls of fluid-filled bodily cavities, such as of the cardiovascular system), for example, the In.Pact Admiral® DCB drug-coated balloon by Medtronic (Dublin, Ireland) and Lutonix® 035 by C. R. Bard, Inc. (Murray Hill, New Jersey, USA).
  • in-situ formed depots examples include semi-solid polymers which can be injected as a melt and form a depot upon cooling to body temperature or two part systems which gel upon mixing ( Figure 3 a).
  • such compositions can be injected into or in contact with bodily tissue that is to be treated
  • the requirements for a semi-solid ISFDs include low melting or glass transition temperatures in the range of 25-65°C and an intrinsic viscosity in the range of 0.05-0.8 dl/g [12-14]. Below the viscosity threshold of 0.05 dl/g no delayed diffusion could be observed, whereas above 0.8 dl/g the ISFD was no longer injectable using a needle. At injection temperatures above 37°C but below 65°C these polymers behave like viscous fluids which solidify to highly viscous depots. Drugs are incorporated into the molten polymer by mixing without the application of solvents. In the art, it is known to use thermoplastic pastes (TP) can be used to generate a subcutaneous drug reservoir from which diffusion occurs into the systemic circulation.
  • TP thermoplastic pastes
  • thermoplastic paste is used to generate a composition for the sustained release of leptin antagonist from which diffusion occurs into tissue in contact with the composition, thereby effecting sustained-release local administration of the leptin antagonist.
  • In situ cross-linked polymer systems utilize a cross-linked polymer network to control the diffusion of bioactive agents (e.g., leptin antagonists for implementing the teachings herein) over a prolonged period of time, thereby allowing implementation of sustained release compositions comprising leptin antagonists for use in local administration thereof.
  • bioactive agents e.g., leptin antagonists for implementing the teachings herein
  • Use of in situ cross-linking implants necessitate protection of the bioactive agents during the cross-linking reaction. This could be achieved by encapsulation into fast degrading gelatin micro-particles.
  • An ISFD can also be based on polymer precipitation.
  • a water-insoluble and biodegradable polymer is dissolved in a biocompatible organic solvent to which leptin antagonist is added forming a solution or suspension after mixing that constitutes a composition according to the teachings herein.
  • leptin antagonist is added to the body of a subject in need thereof
  • this composition is injected into the body of a subject in need thereof the water miscible organic solvent dissipates and water penetrates into the organic phase. This leads to phase separation and precipitation of the polymer forming a depot at the site of injection.
  • AtrigeleTM ARTIX Laboratories
  • the thus-formed depot is a composition for the sustained release of leptin antagonist from which diffusion occurs into tissue in contact with the composition, thereby effecting sustained-release local administration of the leptin antagonist.
  • Thermally induced gelling systems can also be used as ISFDs. Numerous polymers n show abrupt changes in solubility as a function of environmental temperature.
  • the prototypic thermosensitive polymer is poly(N-isopropyl acryl amide), poly-NIPAAM, which exhibits a rather sharp lower critical solution temperature.
  • Thermoplastic pastes such as the new generation of poly(ortho-esters) developed by
  • AP Pharma can also be used for depot drug delivery.
  • Such pastes include polymers that are semi-solid at room temperature, hence heating for drug incorporation and injection is no longer necessary. Injection is possible through needles no larger than 22 gauge.
  • the leptin antagonist is mixed into the systems in a dry and, therefore, stabilized state. Shrinkage or swelling upon injection is thought to be marginal and, therefore, the initial drug burst is expected to be lower than in the other types of ISFD.
  • An additional advantage is afforded by the self-catalyzed degradation by surface erosion.
  • IFSD compositions are suitable for effecting sustained-release local administration of the leptin antagonist.
  • an IFSD composition can be formulated for sustained-release (SR), extended- release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release.
  • Examples of thin films suitable for release of a leptin antagonist (or polynucleotide encoding same) include polymeric films (for a review of thin films, see Zelikin ACS Nano, 2010, 4 (5), pp 2494-2509; Venkat et al. 2010, Polymer Thin Films for Biomedical Applications, Wiley VCH Verlag GmbH & Co. KGaA, Weinheim).
  • Such thin film carriers can be biodegradable or dissolvable over time.
  • Biodegradable microspheres fabricated from, for example, PGA, PLGA, PLA, or PLLA can also be used for local delivery of a leptin antagonist.
  • Such microspheres can be produced as described by Kim and Park (J Control Release. 2004 Jul 23;98(1):115-25).
  • a balloon such as an angioplasty balloon can also be used to deliver a leptin antagonist to a vascular wall or an inner wall of a heart chamber.
  • Approach for coating/loading a balloon with a peptide are described in EP2643030; US8617136; US8617104; US8617114; WO1997017099; US20110166547 and US20120150142.
  • drug-eluting balloons for use for localized delivery of active-pharmaceutical ingredients are well known in the art, for example, the In.Pact Admiral® drug-coated balloon by Medtronic (Dublin, Ireland) and Lutonix® 035 by C. R. Bard, Inc. (Murray Hill, New Jersey, USA). It is important to note that such drug-eluting balloons are known to administer extended release compositions of active pharmaceutical ingredients, e.g., In.Pact Admiral delivers a composition that provides extended release of a continuous therapeutic dose of Paclitaxel for over 180 days.
  • leptin or leptin receptor binding agents such as those described above (or expression thereof in cardiovascular cells)
  • downregulation of leptin activity at specific tissues can also be effected at the transcript level using a variety of molecules that interfere with transcription and/or translation (e.g., antisense, siRNA, Ribozyme, or DNAzyme).
  • RNA interference can be used to downregulate endogenous leptin via a small interfering RNA (siRNA) molecule.
  • siRNA small interfering RNA
  • RNAi is a two-step process, in the first, the initiation step, input double-stranded (dsRNA) is digested into 21- to 23-nucleotide (nt) small interfering RNAs (siRNAs), probably by the action of Dicer, a member of the RNase III family of dsRNA-specific ribonucleases, which processes (cleaves) dsRNA (introduced directly or by means of a transgene or a virus) in an ATP-dependent manner.
  • dsRNA input double-stranded
  • nt small interfering RNAs
  • RNAi Nature abhors a double-strand. Curr Opin Gen Dev 12, 225-232; and Bernstein, E. (2001). Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363-366).
  • the siRNA duplexes bind to a nuclease complex to form the RNA-induced silencing complex (RISC).
  • RISC RNA-induced silencing complex
  • An ATP-dependent unwinding of the siRNA duplex is required for activation of the RISC.
  • the active RISC targets the homologous transcript by base-pairing interactions and cleaves the mRNA into 12-nucleotide fragments from the 3 ' terminus of the siRNA (Hutvagner and Zamore (2002); Hammond et al. (2001) Nat. Rev. Gen. 2:110-119 (2001); and Sharp, P. A. (2001). RNA interference. Genes Dev 15, 485-490). Although the mechanism of cleavage remainsl to be elucidated, research indicates that each RISC contains a single siRNA and an RNase (Hutvagner and Zamore (2002)).
  • RNAi molecules suitable for use with the present invention can be effected as follows. First, the leptin mRNA sequence is scanned downstream of the AUG start codon for AA-dinucleotide sequences. Occurrence of each AA and the 19 3 '-adjacent nucleotides is recorded as a potential siRNA target site.
  • siRNA target sites are selected from the open reading frame (ORF), as untranslated regions (UTRs) are richer in regulatory protein binding sites. UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNA endonuclease complex (Tuschl (2001)).
  • siRNAs directed at untranslated regions may also be effective, as demonstrated for GAPDH, wherein siRNA directed at the 5' UTR mediated about a 90% decrease in cellular GAPDH mRNA and completely abolished protein levels (wwwdotambiondotcom/techlib/tn/91/912dothtml).
  • potential target sites are compared to an appropriate genomic database (e.g., human, mouse, rat, etc.) using any sequence alignment software, such as the BlastN software available from the NCBI server (wwwdotncbidotnlmdotnihdotgov/BLAST/). Putative target sites that exhibit significant homology to other coding sequences are filtered out.
  • an appropriate genomic database e.g., human, mouse, rat, etc.
  • sequence alignment software available from the NCBI server (wwwdotncbidotnlmdotnihdotgov/BLAST/).
  • Qualifying target sequences are selected as templates for siRNA synthesis.
  • Preferred sequences are those including low G/C content, as these have proven to be more effective in mediating gene silencing as compared with sequences including G/C content higher than 55%.
  • Several target sites are preferably selected along the length of the target gene for evaluation.
  • a negative control is preferably used in conjunction.
  • Negative-control siRNAs preferably include the same nucleotide composition as the siRNAs but lack significant homology to the genome. Thus, a scrambled nucleotide sequence of the siRNA is preferably used, provided it does not display any significant homology to any other gene.
  • DNAzyme molecule Another agent capable of downregulating leptin is a DNAzyme molecule, which is capable of specifically cleaving an mRNA transcript or a DNA sequence of the leptin.
  • DNAzymes are single-stranded polynucleotides that are capable of cleaving both single- and double-stranded target sequences (Breaker, R. R. and Joyce, G. F. (1995).
  • a DNA enzyme with Mg 2+ -dependent RNA phosphoesterase activity Curr Biol 2, 655-660; Santoro, S. W. and Joyce, G. F. (1997).
  • a general purpose RNA-cleaving DNA enzyme Proc Natl Acad Sci USA 94, 4262-4266).
  • DNAzymes have a catalytic domain of 15 deoxyribonucleotides, flanked by two substrate-recognition domains of seven to nine deoxyribonucleotides each.
  • This type of DNAzyme can effectively cleave its substrate RNA at purine :pyrimidine junctions (Santoro and Joyce (1997)); for review of DNAzymes, see: Khachigian, L. M. (2002). DNAzymes: cutting a path to a new class of therapeutics.Curr Opin Mol Ther 4, 119-121.
  • DNAzymes complementary to bcr-abl oncogenes were successful in inhibiting the oncogene's expression in leukemia cells, and in reducing relapse rates in autologous bone marrow transplants in cases of Chronic Myelogenous Leukemia (CML) and Acute Lymphoblastic Leukemia(ALL).
  • CML Chronic Myelogenous Leukemia
  • ALL Acute Lymphoblastic Leukemia
  • Downregulation of leptin can also be effected by using an antisense polynucleotide capable of specifically hybridizing with an mR A transcript encoding leptin.
  • the first aspect is delivery of the oligonucleotide into the cytoplasm of the appropriate cells, while the second aspect is design of an oligonucleotide that specifically binds the designated mRNA within cells in a manner inhibiting the translation thereof.
  • Ribozyme molecule capable of specifically cleaving an mRNA transcript encoding leptin.
  • Ribozymes increasingly are being used for the sequence-specific inhibition of gene expression by the cleavage of mRNAs encoding proteins of interest (Welch, P. J. et al. (1998). Expression of ribozymes in gene transfer systems to modulate target RNA levels. Curr Opin Biotechnol 9, 486-496).
  • TFOs triplex-forming oligonucleotides
  • the present invention can be used to treat cardiovascular disorders affecting heart or vascular tissue.
  • the following describes several option for local delivery of a leptin antagonist to tissue, for example heart and other cardiovascular tissue, specifically muscle and valve tissue.
  • Arterial catheterization can be used to deploy a medical device such as a mesh, a thin film, a biodegradable scaffold, a stent cover, a stent, a graft assembly, a coil, a stent, a ring or a prosthetic cardiac valve loaded with a leptin antagonist against a luminal wall of an ascending aorta distal to the orifice of the coronary arteries.
  • a medical device such as a mesh, a thin film, a biodegradable scaffold, a stent cover, a stent, a graft assembly, a coil, a stent, a ring or a prosthetic cardiac valve loaded with a leptin antagonist against a luminal wall of an ascending aorta distal to the orifice of the coronary arteries.
  • a medical device such as a mesh, a thin film, a biodegradable scaffold, a stent cover, a stent,
  • An IFSD (for example, as described above, e.g., a gel) loaded with a leptin antagonist can be delivered via a balloon or needle to the aortic wall.
  • the leptin antagonist extended release film or mesh can be applied via open surgery or minimally invasive laparoscopy.
  • a method of treatment comprising: exposing in vivo tissue of a subject in need thereof to a pharmaceutically-effective amount of leptin antagonist thereby providing a therapeutic effect to the tissue.
  • a composition comprising leptin antagonist is administered (e.g., by injection) directly into the tissue.
  • the exposing of the in vivo tissue to the leptin antagonist is substantially continuously for a period of not less than three days. In some embodiments, the period is not less than five days, not less than 8 days and even not less than 14 days.
  • an extended release composition comprising leptin antagonist e.g., a medical device impregnated with, coated with or made from a leptin antagonist is placed directly in contact with the tissue.
  • a method of treatment comprising implanting in contact with tissue in need thereof in the body of a subject a composition configured for the in vivo release of leptin antagonist, thereby providing a therapeutic effect to the tissue.
  • the composition is configured for sustained release of the leptin antagonist.
  • the implanting is intracavitary implanting within a fluid-filled bodily cavity of the subject.
  • sustained release is meant that, when the composition is implanted in vivo, leptin antagonist is released from the composition in pharmaceutically effective amounts for a period of not less than three days, in some embodiments not less than five days, not less than 8 days and even not less than 14 days.
  • the subject in need thereof is any suitable mammalian subject.
  • the subject is a non-human animal.
  • the subject is a human.
  • the need is any suitable need.
  • the need is at least one need selected from the group consisting of: attenuating a pathology; reducing the chance of developing a pathology; reducing the rate of development a pathology; and mitigating the effect of a pathology.
  • the pathology is any pathology that can be treated by local administration of leptin antagonist, and in some embodiments, substantial continuous local exposure to leptin antagonist.
  • the pathology is at least one pathology selected from the group consisting of:
  • ascending aortic aneurysm in some embodiments ascending aortic aneurysm associated with at least one member of the group consisting of hypertension, dyslipidemia, hypercholesterolemia, obesity, diabetes mellitus and bicuspid aortic valve (BAV);
  • BAV bicuspid aortic valve
  • thoracic aortic aneurysm e.g., to prevent rupture or dissection thereof
  • Takayasu disease e.g., to attenuate cellular proliferative response, in some embodiments, by administration or implantation of a leptin antagonist composition to an inner or outer vessel wall in the vicinity of a vascular lesion;
  • Rheumatoid arteritis e.g., to attenuate cellular proliferative response, in some embodiments, by administration or implantation of a leptin antagonist composition to an inner or outer vessel wall in the vicinity of a vascular lesion;
  • Marian's syndrome by mitigation or prevention of ascending aortic aneurysms or pulmonary artery aneurysms, in some embodiments, by perivascular administration or deployment of a leptin antagonist composition to the outer or inner wall of the ascending aorta); giant cell arteritis; ankylosing spondylitis; inflammatory aortic aneurysm; peripheral arterial or venous aneurysms; prevention of arterial dilatation at site of anchorage of bridging stent grafts ("landing zone") applied for EVAR (in the abdominal or thoracic aorta),visceral or peripheral arteries; prevention of myointimal hyperplasia at sites of vascular injury; prevention of restenosis following PTA or PTCA (peripheral or cardiac balloon angioplasty); angiogenesis; cancer; and arteriovenous malformation (e.g., administration of leptin antagonist composition directly into a malformation or into the feeding artery).
  • any pathology may be treated in accordance with the teachings herein by local administration of leptin antagonist.
  • administration is local administration of a dose (optionally repeated) of leptin antagonist, for example by direct injection into the affected tissue or tissue proximal to the affected tissue or with the use of a drug-eluting balloon.
  • administration is local administration by a sustained release composition (that releases a pharmaceutically-effective amount of leptin antagonist for a period of not less than three days) placed in contact with an outer surface of tissue (e.g., with tunica externa), inside the tissue (e.g., injection of a IFSD as described above into the tissue) or with a composition placed in contact with an inner surface of a tissue (e.g. with tunica intima).
  • a sustained release composition that releases a pharmaceutically-effective amount of leptin antagonist for a period of not less than three days
  • an outer surface of tissue e.g., with tunica externa
  • inside the tissue e.g., injection of a IFSD as described above into the tissue
  • a composition placed in contact with an inner surface of a tissue (e.g. with tunica intima).
  • the tissue is any suitable tissue.
  • the tissue is part of the cardiovascular system.
  • the tissue is selected from the group consisting of arteries, coronary arteries, ascending aorta, abdominal aorta, mitral valve, aortic valve and pulmonary valve.
  • the tissue is cardiovascular tissue with accumulated plaque, for example, an artery with accumulated plaque.
  • the tissue is a tumor, especially a cancerous tumor that grows or spreads in a process that includes angiogenesis.
  • the tissue is an arteriovenous malformation.
  • the leptin antagonist composition is locally administered during or post surgery, e.g., following carotid thrombendartrectomy or after ablation of atherosclerotic occlusion from a vessel.
  • the leptin antagonist is locally administered by contact to the outside of tissue to be treated, e.g., in contact with tunica externa.
  • the leptin antagonist is locally administered inside tissue, for example, is injected or implanted inside tissue such as a tumor or the site of arteriovenous malformation.
  • the leptin antagonist is locally administered intraluminally, e.g., a leptin antagonist composition is deployed in contact with a tunica intima, inside a fluid-filled bodily cavity such as inside the lumen of a blood vessel e.g., using an intraluminal catheter, for example, in conjunction with a stent or prosthetic cardiac valve.
  • local administration of a leptin antagonist in accordance with the teachings herein at the ascending aorta may be effective in attenuating ascending aortic aneurysms, as well as moderating left ventricular hypertrophy, and left heart valve thickness (aortic and mitral).
  • Administration of leptin antagonist at arterial aneurysms in other locations is anticipated to achieve a similar outcome, attenuating aneurysm expansion.
  • embodiments of the teachings herein are used to treat cardiovascular disorders such as heart valve stenosis, arterial or venous aneurysms, or left ventricular remodeling by enabling localized release of a leptin antagonist at the site of treatment.
  • a pharmaceutical composition comprising: as an active ingredient a leptin antagonist; and a pharmaceutically acceptable carrier configured for in vivo sustained release of the leptin antagonist.
  • a method of making a pharmaceutical composition comprising: combining a leptin antagonist; and a pharmaceutically acceptable carrier configured for in vivo sustained release of the leptin antagonist.
  • sustained release is meant that, when the composition is implanted in vivo, leptin antagonist is released from the composition in pharmaceutically effective amounts for a period of not less than three days, in some embodiments not less than five days, not less than 8 days and even not less than 14 days.
  • the in vivo implantation is in a human subject.
  • the in vivo implantation is in any suitable location.
  • the in vivo implantation is contacting an organ through a serous tissue layer or adventitia (tunica externa) layer covering the organ, e.g., is placed contacting a blood vessel such as the aorta from the outside of the blood vessel.
  • the in vivo implantation is outside an organ directly contacting tissue of the organ (for organs covered with serous tissue, the composition is implanted underneath the serous tissue).
  • the in vivo implantation is into an organ.
  • the implantation is from inside a hollow defined by the organ, for example, inside a blood vessel lumen contacting the endothelium thereof.
  • the composition is in the form of a leptin antagonist containing sheet, in some such embodiments configured to be contacted with in vivo tissue, for example, by suturing, with the use of biological adhesive, or pressed against the tissue, for example with the help of a stent or such component, e.g., the sheet is used as a stent cover for a balloon-expandable or self-expanding stent.
  • the composition is configured to coat or be supported by an implantable medical device, e.g., is used as a coating for, is adsorbed or absorbed into or onto a stent (thereby constituting a drug-eluting balloon expandable or self-expanding stent), prosthetic valve (e.g., cardiac valve), implantable spike or rod.
  • an implantable medical device e.g., is used as a coating for, is adsorbed or absorbed into or onto a stent (thereby constituting a drug-eluting balloon expandable or self-expanding stent), prosthetic valve (e.g., cardiac valve), implantable spike or rod.
  • the composition is formed into the shape of an implantable medical device, e.g., a bioresorbable stent, a bioresorbable spike or rod.
  • an implantable medical device e.g., a bioresorbable stent, a bioresorbable spike or rod.
  • the composition is injectable, e.g., is a viscous fluid or a fluid that subsequent to injection solidifies or gels, e.g., a hydrogel.
  • the carrier comprises a biodegradable polymer.
  • the carrier comprises a polymer selected from the group consisting of a hydrogel, poly glycolic acid (PGA), poly lactic co-glycolic acid (PLGA), polylactide (PLA), and poly (L-lactide) (PLLA), and combinations thereof.
  • compositions are in accordance with those known in the art of pharmacology, using any suitable method or combination of methods as known in the art such as described in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference. Such methods include conventional mixing, curing, polymerizing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing.
  • Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the leptin antagonist into a pharmaceutical composition.
  • a use of a leptin antagonist according to the teachings herein for the localized treatment of tissue of a living organism comprising, implanting a composition comprising a leptin antagonist in vivo to contact tissue in need thereof so that the tissue is exposed to a pharmaceutically effective amount of leptin antagonist, thereby providing a therapeutic effect to the tissue.
  • the composition and the implanting is such that the tissue is exposed to a pharmaceutically effective amount of leptin antagonist substantially continuously for a period of at least three days. In some embodiments, the period is not less than five days, not less than 8 days and even not less than 14 days.
  • an above administration is periodically repeated.
  • administration of leptin antagonist is repeated.
  • administration of leptin antagonist is repeated after at least a period, the period selected from the group consisting of 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months and 3 months.
  • stable athersclerotic plaque accumulates in the inner walls of mammalian arteries.
  • the stable plaque transforms into an unstable lesion such as vulnerable plaque or rupture-prone plaque.
  • the unstable lesion may disintegrate, forming emboli.
  • An aspect of the teachings herein is based on the Inventor's discovery that locally synthesized leptin within the carotid atherosclerotic plaque, which characterize unstable plaques (rupture prone), correlates with brain emboli. Therefore, the Inventor believes that a leptin antagonist administered to a stable athersclerotic plaque should reduce the rate and/or incidence of the conversion of a stable athersclerotic plaque to an unstable lesion.
  • a method for treatment of athersclerotic plaque comprising: administering a pharmaceutically-effective amount of a leptin antagonist to athersclerotic plaque accumulated in the inner walls of an artery, thereby at least one of: (a) reducing the rate and (b) reducing the incidence, of conversion of a stable athersclerotic plaque to an unstable lesion.
  • the administration is by sustained-release of the leptin antagonist directly to an inner wall in which plaque is accumulated, from a leptin antagonist containing composition.
  • sustained release is substantial continuous release of a pharmaceutically-effective amount of leptin antagonist for a period of not less than three days, not less than 5 days, not less than 8 days and even not less than 14 days.
  • the composition is in direct contact with the surface of the plaque to be treated.
  • the composition is in contact with the inner walls of a blood vessel with accumulated plaque.
  • MIH myointimal hyperplasia
  • surgical connecting devices such as surgical staples and suture threads that are applied to blood vessels, for example, during surgery for example surgical anastomosis. It has been found that in some instances, local administration of leptin antagonist to such wounds may be able to mitigate or prevent MIH.
  • a surgical connecting device comprising: a solid device body made of a material; and functionally associated with the device body, a pharmaceutically-effective amount of leptin antagonist.
  • the device body is in the form selected from the group consisting of surgical suture thread and a surgical staple.
  • FIG. 27 An embodiment of a suture thread 10 and of a surgical staple 12 in accordance with the teachings herein are schematically depicted in Figure 27.
  • the device body e.g., of thread 10 or staple 12
  • is absorbable i.e., bioresorbable
  • the device body e.g., of thread 10 or staple 12 is made of any suitable material.
  • the device body is made of a material comprises a polymer selected from the group consisting of poly glycolic acid (PGA), poly lactic co-glycolic acid (PLGA), polylactide (PLA), and poly (L-lactide) (PLLA), and combinations thereof.
  • PGA poly glycolic acid
  • PLGA poly lactic co-glycolic acid
  • PLA polylactide
  • PLLA poly (L-lactide)
  • the leptin antagonist is functionally associated with the device body, e.g., of thread 10 or staple 12, in any suitable manner.
  • the functional association of the leptin antagonist with the device body is that a composition comprising the leptin antagonist coats the device body.
  • thread 10 or staple 12 are made of PGA, and coated with a coating of PLGA that includes a pharmaceutically effective amount of leptin antagonist.
  • the functional association of the leptin antagonist with the device body is that a composition comprising the leptin antagonist impregantes the device body.
  • thread 10 is made of silk and impregnated with a composition that includes a pharmaceutically effective amount of leptin antagonist.
  • the functional association of the leptin antagonist with the device body is that the material from which the device body is made is a composition comprising the leptin antagonist.
  • thread 10 or staple 12 are made of PGA that includes a pharmaceutically effective amount of leptin antagonist.
  • Administration of leptin antagonist in fluid-filled cavities is that the material from which the device body is made.
  • a fluid-filled cavity of the body for example of the cardiovascular system such as blood vessels or cardiac chambers
  • a desirable pharmaceutical effect on tissue in proximity of the implanted composition with limited or no substantial side-effects:
  • a method of treating a condition in a subject in need thereof comprising administering intracavitarily to inner walls of a fluid-filled bodily cavity of the subject a composition comprising a leptin antagonist.
  • the subject is human.
  • the subject is a non-human animal.
  • the intracavitary administration exposes in vivo tissue to a pharmaceutically-effective amount of the leptin antagonist and thereby provides a therapeutic effect to the in vivo tissue.
  • the in vivo tissue comprises tissue of the inner walls of the cavity (e.g., tunica intima).
  • the administration is local administration.
  • the in vivo tissue exposed to the pharmaceutically-effective amount of the leptin antagonist is exclusively tissue in physical proximity to the administered composition.
  • the in vivo tissue exposed to the pharmaceutically- effective amount of the leptin antagonist is exclusively tissue in physical contact with the administered composition.
  • exposing of the in vivo tissue to a pharmaceutically-effective amount of the leptin antagonist is substantially continuously for a period of at least three days, at least five days, at least eight days and in some embodiments, even at least fourteen days.
  • the composition is a sustained-release composition, configured for sustained release of a pharmaceutically-effective amount of the leptin antagonist when located inside a bodily cavity.
  • the sustained release comprises release of a pharmaceutically-effective amount of the leptin antagonist over a period of at least three days, at least five days, at least eight days and in some embodiments, even at least fourteen days.
  • the intracavitary administering comprises implantation of the composition within the cavity in contact with the inner walls of the cavity.
  • the intracavitary administering comprises deploying an intracavitarily-implantable medical device in the cavity.
  • the medical device is deployed in contact with the inner walls of the cavity.
  • the leptin antagonist is functionally associated with the deployed intracavitarily-implantable medical device.
  • the leptin antagonist is functionally associated with a portion of the deployed intracavitarily- implantable medical device that contacts bodily tissue when the medical device is deployed.
  • the intracavitarily implantable medical device is selected from the group consisting of: a stent cover, a graft assembly, a coil (e.g., aneurysm coil), a stent (e.g., expandable stent, self-expanding stent, covered stent, partially covered stent, not covered stent), a ring (e.g, a graft anchor), a suture, a staple and a prosthetic cardiac valve.
  • a stent cover e.g., a graft assembly
  • a coil e.g., aneurysm coil
  • a stent e.g., expandable stent, self-expanding stent, covered stent, partially covered stent, not covered stent
  • a ring e.g, a graft anchor
  • teachings herein are applicable to any prosthetic cardiac valve, the teachings are particularly advantageous for implementing with catheter-deployed prosthetic cardiac valves (e.g., TAMVI, TAVI): since these valves are typically held in place without sutures so that myointimal hyperplasia that potentially develops as a result of trauma caused during deployment may lead to leakage.
  • catheter-deployed prosthetic cardiac valves e.g., TAMVI, TAVI
  • compositions comprising: a leptin antagonist for use in treating a condition, wherein the composition is configured for intracavitary administration to inner walls of a fluid-filled bodily cavity of a subject.
  • the subject is human.
  • the subject is a non-human animal.
  • the intracavitary administration of the composition exposes in vivo tissue to a pharmaceutically-effective amount of the leptin antagonist, thereby providing a therapeutic effect to the in vivo tissue.
  • such in vivo tissue comprises tissue of inner walls of a the cavity.
  • the administration is local administration.
  • the in vivo tissue exposed to the pharmaceutically-effective amount of the leptin antagonist is exclusively tissue in physical proximity to the administered composition.
  • the in vivo tissue exposed to the pharmaceutically-effective amount of the leptin antagonist is exclusively tissue in physical contact with the administered composition.
  • exposing of the in vivo tissue to a pharmaceutically-effective amount of the leptin antagonist is substantially continuously for a period of at least three days, at least five days, at least eight days and in some embodiments, even at least fourteen days.
  • the composition is a sustained-release composition, configured for sustained release of a pharmaceutically-effective amount of the leptin antagonist when located inside a bodily cavity.
  • the sustained release comprises release of a pharmaceutically-effective amount of the leptin antagonist over a period of at least three days, at least five days, at least eight days and in some embodiments, even at least fourteen days.
  • the configuration for intracavitary administration comprises configuration for implantation of the composition within the cavity in contact with the inner walls of the cavity.
  • the configuration for intracavitary administration comprises configuration for deploying with an intracavitarily-implantable medical device in the cavity.
  • the medical device is configured for deployment in contact with the inner walls of the cavity.
  • the leptin antagonist is functionally associated with the intracavitarily-implantable medical device.
  • the leptin antagonist is functionally associated with a portion of the intracavitarily-implantable medical device that contacts bodily tissue when the medical device is deployed.
  • the intracavitarily implantable medical device is selected from the group consisting of: a stent cover, a graft assembly, a coil (e.g., aneurysm coil), a stent (e.g., expandable stent, self-expanding stent, covered stent, partially covered stent, not covered stent), a ring (e.g, a graft anchor), a suture, a staple and a prosthetic cardiac valve.
  • a stent cover e.g., a graft assembly
  • a coil e.g., aneurysm coil
  • a stent e.g., expandable stent, self-expanding stent, covered stent, partially covered stent, not covered stent
  • a ring e.g, a graft anchor
  • suture e.g., a staple and a prosthetic cardiac valve.
  • the condition is a pathological cardiovascular condition.
  • the condition is a cardiovascular condition selected from the group consisting of atherosclerosis, valve stenosis, aneurysms, vessel response to vascular injury, and cardiomyopathy.
  • the administration of the leptin antagonist is to athersclerotic plaque accumulated in the inner walls of an artery, thereby at least one of: (a) reducing the rate and (b) reducing the incidence, of conversion of a stable athersclerotic plaque to an unstable lesion.
  • the administration of the leptin antagonist is to bodily tissue in order to prevent or mitigate the development of myointimal hyperplasia, for example, myointimal hyperplasia that potentially develops as a result of trauma caused during deployment of a medical device in a the body of a living subject.
  • the composition constitutes a coating of an intracavitarily implantable medical device.
  • the composition is impregnated in an intracavitarily implantable medical device.
  • the composition comprises, in addition to the leptin antagonist, a polymer selected from the group consisting of a hydrogel, poly glycolic acid (PGA), poly lactic co-glycolic acid (PLGA), polylactide (PLA), and poly (L-lactide) (PLLA), and combinations thereof.
  • the composition is in the form selected from the group consisting of a sheet and a tube constituting a portion of an intracavitarily implantable medical device comprising the leptin antagonist.
  • the composition comprises, in addition to the leptin antagonist, a polymer selected from the group consisting of of a hydrogel, poly glycolic acid (PGA), poly lactic co-glycolic acid (PLGA), polylactide (PLA), and poly (L-lactide) (PLLA), and combinations thereof.
  • the intracavitarily implantable medical device comprises a stent and the composition constitutes a stent cover (e.g., a partial or complete stent cover, a balloon-expandable or a self-expanding stent).
  • the intracavitarily implantable medical device comprises a graft-assembly (e.g., a stent-graft or ring-graft assembly) and the composition constitutes a graft portion thereof.
  • some embodiments are configured to function as a stent-graft assembly for treatment of AAA, like the Endurant® II by Medtronic (Dublin, Ireland).
  • the composition constitutes at least a portion of an intracavitarily implantable medical device, and in some embodiments, the composition constitutes substantially an entire intracavitarily implantable medical device.
  • the intracavitarily implantable medical device is selected from the group consisting of a stent cover, a graft assembly, a coil (e.g., aneurysm coil), a stent (e.g., expandable stent, self-expanding stent, covered stent, partially covered stent, not covered stent), a ring (e.g, a graft anchor), a suture, a staple and a prosthetic cardiac valve.
  • a stent cover e.g., a graft assembly
  • a coil e.g., aneurysm coil
  • a stent e.g., expandable stent, self-expanding stent, covered stent, partially covered stent, not covered stent
  • the composition comprises, in addition to the leptin antagonist, a polymer selected from the group consisting of a hydrogel, poly glycolic acid (PGA), poly lactic co- glycolic acid (PLGA), polylactide (PLA), and poly (L-lactide) (PLLA), and combinations thereof.
  • a polymer selected from the group consisting of a hydrogel, poly glycolic acid (PGA), poly lactic co- glycolic acid (PLGA), polylactide (PLA), and poly (L-lactide) (PLLA), and combinations thereof.
  • an intracavitarily-implantable medical device comprising:
  • At least one solid functional device part configured for deploying the device in a fluid- filled bodily cavity of a subject
  • a leptin antagonist functionally associated with at least one the device component, a leptin antagonist.
  • the leptin antagonist is functionally associated with the at least one the device part as a component of a pharmaceutical composition comprising the leptin antagonist.
  • the pharmaceutical composition is a sustained-release composition, configured for sustained release of a pharmaceutically- effective amount of the leptin antagonist when located inside a bodily cavity.
  • sustained release comprises release of a pharmaceutically-effective amount of the leptin antagonist over a period of at least three days, at least five days, at least eight days and in some embodiments, even at least fourteen days.
  • the pharmaceutically-acceptable carrier further comprises a polymer selected from the group consisting of a hydrogel, poly glycolic acid (PGA), poly lactic co-glycolic acid (PLGA), polylactide (PLA), and poly (L-lactide) (PLLA), and combinations thereof.
  • PGA poly glycolic acid
  • PLGA poly lactic co-glycolic acid
  • PLA polylactide
  • PLLA poly (L-lactide)
  • the functional association is at least one device component having a coating comprising the pharmaceutical composition. In some embodiments of the medical device, the functional association is at least one device component being impregnated with the pharmaceutical composition. In some embodiments of the medical device, the functional association is at least one device component being fashioned of the pharmaceutical composition.
  • the medical device is selected from the group consisting of a stent cover, a graft assembly, a coil (e.g., aneurysm coil), a stent (e.g., expandable stent, self-expanding stent, covered stent, partially covered stent, not covered stent), a ring (e.g, a graft anchor), a suture, a staple and a prosthetic cardiac valve (as noted above, preferably catheter-deployed prosthetic cardiac valves.
  • a stent cover e.g., a graft assembly
  • a coil e.g., aneurysm coil
  • a stent e.g., expandable stent, self-expanding stent, covered stent, partially covered stent, not covered stent
  • a ring e.g, a graft anchor
  • a suture a staple and a prosthetic cardiac valve (as noted
  • the fluid-filled bodily cavity is a bodily cavity of the cardiovascular system.
  • the cavity is selected from the group consisting of a cardiac chamber, an artery and a vein.
  • the cardiac chamber is selected from the group consisting of left ventricle, right ventricle, left atrium and right atrium.
  • the artery is selected from the group consisting of a systemic artery, a cardiac artery and a pulmonary artery.
  • the systemic artery is an aorta, for example selected from the group consisting of an ascending aorta, aortic arch, descending aorta and an abdominal aorta.
  • an aneurysm coil 14 according to the teachings herein is schematically depicted.
  • Aneurysm coil 14 is substantially similar to known aneurysm coils except by being functionally associated with a pharmaceutically-effective amount of leptin antagonist, is made in substantially the same way, and is used in substantially the same way.
  • a given aneurysm coil 14 may include one or more of the additional features detailed hereinabove.
  • coil 14 is made of platinum, and coated with a coating of a hydrogel that includes a pharmaceutically effective amount of leptin antagonist.
  • coil 14 is made of a material such as platinum or a polymer textured with micrometer dimension features such as valleys and pores, where inside the features is held a composition (e.g., a gel such as of Example 11) that comprises leptin antagonist.
  • a composition e.g., a gel such as of Example 11
  • coil 14 is made of a composition comprising the leptin antagonist, e.g., is made of PGA that includes a pharmaceutically effective amount of leptin antagonist.
  • Prosthetic cardiac valve 16 is substantially similar to known prosthetic cardiac valves except by being functionally associated with a pharmaceutically- effective amount of leptin antagonist, is made in substantially the same way, and is used in substantially the same way.
  • prosthetic cardiac valve 16 has at least one component that is functionally associated with a pharmaceutically-effective amount of leptin antagonist.
  • a given prosthetic cardiac valve 16 according to the teachings herein may include one or more components, each having one or more of the additional features detailed hereinabove.
  • the retainer ring of prosthetic cardiac valve 16 is made of a cobalt chromium ring with a polyester cloth cover, the ring and cloth cover both coated with a coating of a hydrogel that includes a pharmaceutically effective amount of leptin antagonist.
  • the leaflets of prosthetic cardiac valve 16 are made of a material such as porcine or bovine tissue (e.g., cardiac leaflets, pericardium) that has been soaked in and is therefore impregnated with a composition (e.g., a gel such as of Example 11) that comprises leptin antagonist.
  • Graft assembly 18 is a ring-graft assembly suitable for treatment of abdominal aorta aneurysms and includes a flexible graft 20 that defines a conduit for blood flow and three expandable anchoring rings 22 as graft anchors.
  • Each anchoring ring 22 is a radially expandable device that is substantially a single 360° ring of material.
  • some embodiments of graft assemblies are stent-graft assemblies where one or more of the anchors are radially expandable stents, that are longer in the axial direction and/or describe more than a 360° degree rotation and/or comprise more than a single ring of material.
  • Graft assembly 18 is substantially similar to known graft assemblies except by being functionally associated with a pharmaceutically-effective amount of leptin antagonist, is made in substantially the same way, and is used in substantially the same way. Specifically, graft assembly 18 has at least one component that is functionally associated with a pharmaceutically-effective amount of leptin antagonist.
  • a given graft assembly 18 may include one or more components, each having one or more of the additional features detailed hereinabove.
  • graft 20 is substantially a tube made of a high- density multifilament polyester cloth coated with a coating of a hydrogel that includes a pharmaceutically effective amount of leptin antagonist.
  • the coating is on the entire outer surface of graft 20.
  • the coating is on the outer surface of the termini of the three legs of graft 20 (e.g., a 5 cm length from each terminus.
  • graft 20 is made of a high-density multifilament polyester cloth coat that has been soaked in and is therefore impregnated with a composition (e.g., a gel such as of Example 11) that comprises leptin antagonist.
  • a composition e.g., a gel such as of Example 11
  • the entire graft 20 is impregnated with leptin antagonist composition.
  • only the termini of the three legs of graft 20 e.g., a 5 cm length from each terminus is impregnated with leptin antagonist composition.
  • rings 22 are made of nitinol, and coated with a coating of a hydrogel that includes a pharmaceutically effective amount of leptin antagonist.
  • rings 22 are made of a material such as nitinol textured with micrometer dimension features such as valleys and pores, where inside the features is held a composition (e.g., a gel such as of Example 11) that comprises leptin antagonist.
  • Stents 24, 26 and 28 are all elongated, tubular, outwardly radially-expandable frameworks that are known in the art.
  • Stent 24 is a coverless stent without a cover.
  • Stent 26 is a partially-covered stent with a partial cover 30.
  • Partial cover 30 is a sheet secured to the framework of stent 26 in the usual way, e.g., with sutures.
  • Stent 28 is a covered stent with a full cover 32.
  • Full cover 30 is a tube secured to the framework of stent 28 in the usual way, e.g., with sutures or by tension.
  • Stents 24, 26 and 28 are substantially similar to known stents except by being functionally associated with a pharmaceutically-effective amount of leptin antagonist, are made in substantially the same way, and are used in substantially the same way. Specifically, each one of stents 24, 26 and 28 has at least one component that is functionally associated with a pharmaceutically-effective amount of leptin antagonist. Depending on the embodiment, a given stent 24, 26 and 28 according to the teachings herein may include one or more components, each having one or more of the additional features detailed hereinabove. Embodiments of any one of stents 24, 26 and 28 are self-expanding stents. Embodiments of any one of stents 24, 26 and 28 are balloon-expandable stents.
  • a cover 30 or a cover 32 is made of a high- density multifilament polyester cloth coated with a coating of a hydrogel that includes a pharmaceutically effective amount of leptin antagonist, typically on the outer surface of the cover.
  • a cover 30 or a cover 32 is made of a high- density multifilament polyester cloth coated that has been soaked in and is therefore impregnated with a composition (e.g., a gel such as of Example 11) that comprises leptin antagonist.
  • a composition e.g., a gel such as of Example 11
  • a cover 30 or a cover 32 is made of a material that is a composition comprising leptin antagonist, e.g., a PLGA sheet of example 4.
  • a framework of any one of stents 24, 26 and 28 is made of cobalt chromium coated with a coating of a hydrogel that includes a pharmaceutically effective amount of leptin antagonist.
  • a framework of any one of stents 24, 26 and 28 is made of a material such as nitinol or a polymer textured with micrometer dimension features such as valleys and pores, where inside the features is held a composition (e.g., a gel such as of Example 11) that comprises leptin antagonist.
  • a composition e.g., a gel such as of Example 11
  • a framework of any one of stents 24, 26 and 28 is made of a material that is a composition comprising leptin antagonist, e.g., PLA or PLLA comprising a pharmaceutically-effective amount of leptin antagonist.
  • leptin antagonist e.g., PLA or PLLA comprising a pharmaceutically-effective amount of leptin antagonist.
  • leptin antagonist Any suitable leptin antagonist may be used in implementing any specific aspect or embodiment of the teachings herein. In some embodiments, a single leptin antagonist is used. In some embodiments, two or more leptin antagonists are used simultaneously or concurrently.
  • the leptin antagonist comprises a polypeptide portion.
  • the leptin antagonist is a polypeptide.
  • Preferred leptin antagonists include all of the leptin antagonists listed and taught in
  • the leptin antagonist is selected from the group consisting of: a leptin antagonist consisting of: (a) a mammalian leptin polypeptide in which the LDFI (SEQ ID NO:33 in US 7,307,142) hydrophobic binding site at the positions corresponding to positions 39-42 of the wild-type human leptin, is modified such that from two to four amino acid residues of the hydrophobic binding site are substituted with different amino acid residues such that the site becomes less hydrophobic, the modified, mammalian leptin polypeptide being a leptin antagonist; (b) a fragment of the modified mammalian leptin polypeptide of (a) comprising the altered hydrophobic binding site, wherein the fragment is itself a leptin antagonist; (c) a fragment of (b) a synthetic leptin antagonist comprising:
  • a modified mammalian leptin polypeptide in which: (i) the LDFI hydrophobic binding site at the position corresponding to 5 positions 39-42 of the wild-type human leptin is modified such that from two to four amino acid residues of the hydrophobic binding site are substituted with different amino acid residues such that the site becomes less hydrophobic, the modified mammalian leptin polypeptide being a leptin antagonist; and
  • a synthetic leptin agonist comprising: (h) a modified mammalian leptin polypeptide in which D23 is substituted with a different amino acid residue that is not negatively charged or T12 is substituted with a different amino acid residue that is hydrophobic; (j) a fragment of the modified mammalian leptin polypeptide of (h), in which D23 is substituted with a different amino acid residue that is not negatively charged or T12 is substituted with a different amino acid residue that is hydrophobic, wherein the fragment is itself a leptin agonist;
  • intracavitary relates to within an organ or body cavity.
  • a novel mouse model was used to simulate local leptin synthesis in the ascending aorta in order to assess the effect of leptin on aortic remodeling and heart structure and function.
  • a slow release leptin film made of polylactic co-glycolic acid (PLGA) matrix (1 X 1.5 mm), and containing either 2 ⁇ g leptin or no protein (control) was applied to the anterior surface of the proximal ascending aorta ( Figure 4).
  • PLGA polylactic co-glycolic acid
  • the leptin slow-release film was manufactured by impregnating a poly lactic-co- gly colic acid (PLGA) film with leptin.
  • MgCl 2 Fesher Scientific, Loughborough, UK
  • Sodium chloride (10 mg in 0.2 mL distilled water) and 25 xL ethylene glycol (Sigma- Aldrich, St. Louis, MO, USA) were added to the polymeric solution and sonicated for 20 seconds.
  • Mouse leptin powder (1 mg; #L3772; Sigma- Aldrich, St. Louis, MO, USA) was suspended in 2 mL of the polymeric solution, followed by casting on a flat surface of Teflon molds to create a flat film. Films were dried in a hood for 48 hours, and then subjected to high vacuum for 12 hours to extract any residual solvent. Control (placebo) films were fabricated in the same way without the addition of leptin. The calculated amount of leptin per 1 X 1.5-mm film used currently for implantation in each mouse was 2 g.
  • Another option of leptin application for local slow-release has been a gel composed of two liquid materials which gel (solidify) upon mixing at the time of injection. These are a modified carboxymethyl cellulose with adipic dihydrazide (CMC-ADH) and an oxidized dextrane in DDW (DX-COH). Methylene blue dye (0.5%) was also added to the DX-COH solution to make the resulting gel more visible. Leptin (Sigma, L3772, St. Louis, MO, USA) was added to the gel by an emulsion technique.
  • CMC-ADH modified carboxymethyl cellulose with adipic dihydrazide
  • DX-COH oxidized dextrane in DDW
  • Methylene blue dye 0.5%) was also added to the DX-COH solution to make the resulting gel more visible.
  • Leptin Sigma, L3772, St. Louis, MO, USA
  • Serum leptin levels were determined in ApoE "A mice after receiving 20 ⁇ g mouse leptin via peri-aortic application (in another experiment, Tao et al. ATVB 2013). Blood was samples on days 0, 7, 14, and 21, and leptinanalyzeded by ELISA assay (Quantikine Mouse Lep Kit, R&D Systems, Minneapolis, MN, USA): Day 0 - 3.5 ng/mL; day 7 - leptin 8.0 ng/mL, placebo 9.2 ng/mL; day 14 - leptin 12.0 ng/mL, placebo 14.5 ng/mL; and day 21- leptin 12.25 ng/mL, placebo 12.5 ng/mL ( Figure 6).
  • mice in experiment 1 were fed postoperatively with high fat diet (HFD), and were followed up for 45 days.
  • HFD high fat diet
  • Mouse weight and blood pressure (BP) were assessed weekly. All mice recovered from surgery uneventfully.
  • mice gained weight equally during the follow up period, suggesting no systemic leptin effect.
  • Systolic BP measured weekly in mice of experiment 2 was 100 mmHg throughout the first 4 weeks, and increased to 120 mmHg by week 6 in both leptin treated and control mice. Based on two separate experiments, both HFD and normal chow feeding yielded in general similar results.
  • Histological analysis of the ascending aorta revealed features of medial degeneration at the site of leptin application, including fragmentation of the elastic lamellas, as demonstrated by elastica van Giesen staining, and depletion of aSMA in the media (Figure 7). These structural changes likely underlie local stiffening and dilatation in the proximal ascending aorta.
  • PSV peak systolic velocity
  • Angiotensin II is the key hormone of the renin-angiotensin system, underlying hypertension and cardiovascular remodeling (Renna et al. Pathophysiology of vascular remodeling in hypertension. Int J Hypertens. 2013;2013: 808353).
  • the phenotypes induced by local leptin application described in Example 1 are reminiscent of Angll induced aortic-ventricular (coupling) remodeling, suggesting that leptin mediates these processes.
  • a leptin antagonist was delivered locally to the ascending aorta in order to assess the effects of leptin down-regulation on Angll induced local aortic remodeling, and aortic- ventricular remodeling in mice.
  • mice An osmotic mini-pump, delivering Angll at a rate of 1000 ng/kg/min was implanted subcutaneously in the back of the neck of 14 week old ⁇ " mice. Each mouse also underwent left mini-thoracotomy for application of a slow release miniature PLGA film (1x1.5 mm) containing either 5 ⁇ g leptin antagonist (LA), or PLGA matrix devoid of protein (control). The slow release film was deployed on the surface of the proximal ascending aorta at the position described in Experiment 1. Mice were euthanized 4 weeks following surgery.
  • LA leptin antagonist
  • control PLGA matrix devoid of protein
  • mice treated with Angll either Ang II alone or Ang II with control film applied on the ascending aorta.
  • Death was related to thoracic (28%) or abdominal (6%) aortic aneurysm rupture.
  • the PS V parameter is likely reflecting the interaction between proximal aortic hemodynamics, and left ventricular systolic contraction.
  • PSV moderation by LA may represent attenuation of both aortic and LV remodeling.
  • the present findings show that application of a leptin antagonist at the pivotal location on the proximal ascending aortic surface prevents rupture of thoracic aneurysms induced by systemic infusion of Ang II.
  • Local inhibition of leptin activity reduces the degenerative effects of Ang II on the proximal aorta, which underlie aortic wall destabilization.
  • Human AVS and normal arterial valve (AV) samples were collected for analysis, including autopsy samples, freshly collected AVS specimens from patients undergoing aortic valve replacement surgery, and normal aortic valves from explanted hearts.
  • Formalin fixed valve samples were analyzed by immunohistochemistry for leptin, leptin receptor, CD68 and aSMA.
  • Fresh samples of AVS valves and normal aortic valves underwent total RNA extraction and analyzed by qPCR and Nanostring technique to assess leptin and leptin receptor mRNA levels. Retroperitoneal fat was used as a positive control in both assays.
  • VICs human valve interstitial cells
  • Poly lactic-co-glycolic acid (PLGA) films containing a leptin antagonist e.g., a leptin antagonist described in US 8,969,292
  • a leptin antagonist e.g., a leptin antagonist described in US 8,969,292
  • a 2x2.5-mm patch of PLGA film of Example 4 is maintained in 5 mL sterile PBS at 37°C for 28 days. Every 7 days the PBS medium is sampled before being aspirated and replaced by 5 mL of fresh PBS. The medium samples are analyzed by ELISA (RayBiotech, Norcross, GA, USA) for leptin antagonist levels. The in vitro measurement of leptin discharged from the slow-release PLGA film yields substantial release of leptin antagonist for at least two weeks.
  • a first component of the composition is an aqueous solution of modified carboxymethyl cellulose with adipic dihydrazide (CMC-ADH). Dried and finely ground sustained-release gel with leptin antagonist as described in Example 1 is added to the CMC- ADH solution and vortexed to yield a suspension.
  • CMC-ADH modified carboxymethyl cellulose with adipic dihydrazide
  • a second component of the composition is oxidized dextrane in DDW (DX-COH).
  • DX-COH DDW
  • a dye such as methylene blue (0.5%) is optionally added to the DX-COH solution to make the resulting gel more visible.
  • a stent cover is fashioned from the PLGA film of Example 4.
  • the stent cover is used to cover the balloon expandable stents of a MULTI-LINK 8 LL coronary stent system, a MULTI-LINK ULTRA coronary stent system and a MULTI- LINK MINI VISION coronary stent system (all of Abbot Laboratories, Abbot Park, Illinois, USA).
  • the graft (stent cover) portion of an Endurant II AAA Stent Graft System (Medtronic, Dublin, Ireland) is impregnated with a leptin antagonist.
  • impregnation is by immersion in a first component of the composition of Example 3, followed by contact with contact with the second component thereof.
  • the stent cover is used as an external cover for a self-expanding WallFlex Stent (Boston Scientific Corporation, Natick, MA, USA).
  • the covered stents are deployed in the usual way inside the lumen of a blood vessel of a living subject in need thereof. Once implanted, the leptin antagonist elutes from the stent cover through the blood vessel endothelium into the blood vessel to exert a desired pharmaceutical effect.
  • An XIENCE Alpine coronary stent system (Abbot Laboratories, Abbot Park, Illinois, USA) is prepared in the usual way, but impregnated with a leptin antagonist as an active pharmaceutical ingredient instead of Everolimus.
  • the resulting drug-eluting stent is deployed in the usual way inside the lumen of a blood vessel of a living subject in need thereof.
  • the leptin antagonist elutes from the stent through the blood vessel endothelium into the blood vessel to exert a desired pharmaceutical effect.
  • a bioresorbable balloon-expandable stent is fashioned of bioresorbable polylactide (PLA) comprising a leptin antagonist, substantially as done to fashion a bioresorbable stent by Arterial Remodeling Technologies (Paris, France).
  • PLA bioresorbable polylactide
  • a bioresorbable balloon-expandable stent is fashioned of bioresorbable poly (L- lactide) (PLLA) comprising a leptin antagonist and also comprises a bioresorbable coating of PLLA including a leptin antagonist, substantially as done to fashion an Absorb GT1 vascular scaffold stent.
  • PLLA bioresorbable poly (L- lactide)
  • bioresorbable stents are deployed in the usual way inside the lumen of a blood vessel of a living subject in need thereof.
  • the leptin antagonist elutes from the stents as these resorb, to pass through the blood vessel endothelium into the blood vessel to exert a desired pharmaceutical effect.
  • An implantable spike or rod (bioresorbable or not) is made as known in the art, for example as described above with reference to the stents and includes leptin antagonist integrated into the material of the spike or rod, or adsorbed, absorbed or coated onto the spike or rod.
  • the resulting spike or rod is implanted in the usual way inside an organ, for example by piercing the organ. Once implanted, the leptin antagonist elutes from the spike or rod, to exert a desired pharmaceutical effect on the organ.
  • the two components of the composition of Example 3 are provided.
  • the components are mixed together and implanted in the body of the subject by injection into or onto an organ to form a gelled mass in or on the organ.
  • the leptin antagonist elutes from the gelled mass, to exert a desired pharmaceutical effect on the organ.
  • a sheet of the film of Example 1 is provided.
  • the sheet is placed against the outer surface of an organ (e.g., aorta, for example, ascending aorta, aortic arch, descending aorta, abdominal aorta) and optionally held in place by sutures and/or biological glue (e.g., Evicel® by Ethicon of Johnson and Johnson).
  • organ e.g., aorta, for example, ascending aorta, aortic arch, descending aorta, abdominal aorta
  • biological glue e.g., Evicel® by Ethicon of Johnson and Johnson.
  • the leptin antagonist elutes from the film, to exert a desired pharmaceutical effect on the organ.
  • a human subject is diagnosed with an abdominal aortic aneurysm (AAA).
  • AAA abdominal aortic aneurysm
  • a composition according to the teachings herein in the form of a long sheet such as described in Example 12 (a ribbon) comprising leptin antagonist is provided.
  • the abdominal aorta of the subject is surgically accessed from the outside (e.g., using keyhole surgery) and the composition administered by winding the long sheet around the abdominal aorta to wrap the entire aneurysm as well as a portion of the aorta above and below the aneurysm, and held in place with a biological glue and/or sutures.
  • a stent graft e.g., an Endurant® II AAA Stent Graft System (Medtronic, Dublin, Ireland)
  • leptin antagonist from the composition passes through the tunica externa to provide a beneficial effect to the subject,
  • an AAA stent graft is provided that is similar to known AAA stent grafts (e.g., similar to an Endurant® II AAA Stent Graft System (Medtronic, Dublin, Ireland)) where at least one of: the graft and/or anchoring stents are a composition of the teachings herein and comprises a leptin antagonist; at least the anchoring portions of the graft and/or anchoring stents are impregnated with a composition of the teachings herein that comprises a leptin antagonist; and at least the anchoring portions of the graft and/or anchoring stents are coated with a composition of the teachings herein that comprises a leptin antagonist.
  • known AAA stent grafts e.g., similar to an Endurant® II AAA Stent Graft System (Medtronic, Dublin, Ireland)
  • the graft and/or anchoring stents are a composition of the teachings herein and comprises a leptin antagonist
  • the stent-graft is deployed in the usual way in the abdominal aneurysm, that is to say, where the anchoring stents are expanded against healthy portions of tunica intima above and below the aneurysm. Subsequently, leptin antagonist from the composition passes through the tunica intima to provide a beneficial effect to the subject, for example, preventing or reducing the extent that the aneurysm spreads to portions of tissue in proximity of the anchoring stents, thereby preventing loosening of the anchoring stents.
  • a drug-eluting balloon similar to the In.Pact Admiral® DCB drug-coated balloon by Medtronic (Dublin, Ireland) that is coated with a composition comprising leptin antagonist according to the teachings herein is introduced through the femoral arteries and advanced to areas of the abdominal and iliac arteries that are just above and just below the aneurysm (for example, "landing zones" where anchoring stents of a stent- graft would be deployed.
  • the balloon is expanded to contact the aorta and iliac walls, thereby administering composition to the healthy tissue and preventing advancement of the aneurysm.
  • the administration of leptin antagonist is repeated periodically, e.g., with a frequency that is less than once a month, less than once every two months and even less than once every 3 months.
  • the administration of the leptin antagonist leads to stabilization of the wall tissue, halting the processes of aneurysm formation at the portions of the blood vessels above and below the aneurysm and at the portions of the blood vessel in contact with the deployed stent graft.
  • thoracic aortic aneurysm Treatment of thoracic aortic aneurysm A human subject is diagnosed with an aneurysm in the thoracic aorta, including one or more of the ascending aorta, aortic arch and descending aorta. It is known that segmental increased stiffness and aortic dilatation cause local aneurysm formation. These structural changes underlie hemodynamic perturbation, which increases left ventricular afterload. This results in left ventricular remodeling, including left ventricular hypertrophy, and thickening of the aortic and mitral valve leaflets. Left ventricular hypertrophy may lead to heart failure, and aortic valve remodeling may progress to the full clinical presentation of aortic valve stenosis.
  • a composition according to the teachings herein in the form of a patch such as described in Example 12 comprising leptin antagonist is provided.
  • the thoracic aorta of the subject is surgically accessed from the outside (e.g., using thorascopy) and the composition administered by contacting the outer surface of the affected portions of the aorta with the patch, and optionally holding the patch in place with a biological glue and/or sutures.
  • a drug eluting stent graft impregnated with leptin antagonist is deployed in the aneurysm in the usual way, without oversizing.
  • leptin antagonist from the composition passes into the tissue to provide a beneficial effect to the subject, in some embodiments one or more of attenuate aneurysm progression, stablize the vessel wall and prevent rupture or dissection of the aneurysm.
  • the administration of the leptin antagonist also leads to reducing the rate of development, or stopping the development and in some embodiments, reversing the remodeling of parts of the heart.
  • a human subject is diagnosed with arterial stenosis that is treatable by angioplasty.
  • a drug-eluting balloon similar to the In.Pact Admiral® DCB drug-coated balloon by Medtronic (Dublin, Ireland) that is coated with a composition comprising leptin antagonist according to the teachings herein is used in the usual way to perform the angioplasty procedure, for example, at sites of arterial bifurcations and in-stent stenoses.
  • At least some of the composition according to the teachings herein that coats the balloon is administered to the surface of the treated blood vessel, thereby administering a composition according to the teachings herein.
  • the administration of leptin antagonist is repeated periodically, e.g., with a frequency that is less than once a month, Jess than once every two months and even less than once every 3 months, even when there is no express need for repeated angioplasty. Subsequently, leptin antagonist from the composition passes into and/or through the lesion and/or tunica intima to provide a beneficial effect to the subject.
  • composition according to the teachings herein in the form of a stent
  • leptin antagonist from the administered composition passes into and/or through the lesion and/or tunica intima to provide a beneficial effect to the subject.
  • Myocardial infarction causes left ventricular remodeling, leading to progressive impairment of cardiac function.
  • a human subject is diagnosed with an acute myocardial infarction and is treated in the usual way, for example coronary catheterization for primary revascularization and myocardial salvage.
  • a treating health-care professional identifies that the subject has an elevated risk of developing cardiac dysfunction.
  • a composition comprising leptin antagonist is administered to the ascending aorta as described in the preceding examples using one or more of a drug-eluting balloon, a stent, a covered stent and a stent graft. Subsequently, leptin antagonist from the administered composition passes into and/or through the tunica intima of the aorta to provide a beneficial effect to the subject.
  • the beneficial effect is prophylactic, preventing development of or reducing the rate of development of an thoracic aortic aneurysm, and/or remodeling of the heart (in particular the left ventricle and associated valves) and/or a recurring infarction.
  • MIH Myointimal Hyperplasia
  • MACH myointimal hyperplasia
  • Such trauma include vascular injury caused by expansion of a blood vessel during angioplasty, stent deployment, stent-graft deployment, as a result of surgical anastomosis and associated suturing, clamping of blood vessels, and as a result of blunt and/or penetrating vascular injury.
  • a health-care professional identifies that a subject has an elevated risk of developing myointimal hyperplasia due to some vascular trauma, administers a composition comprising leptin antagonist according to the teachings herein to the site of the trauma.
  • the thus administered leptin antagonist reduces the rate or stops the uncontrolled proliferation of cells, reducing the rate of development or preventing MIH.
  • Administration includes the use of any of the compositions according to the teachings herein, including localized administration of a leptin antagonist composition on the outer surface of the blood vessel at the site of injury during surgery (e.g., application of a film of Example 4 as a patch), intravascular administration using a drug eluting balloon, or by administration of a composition that impregnates or coats a medical device, or a composition that is in the shape of a medical device by deploying the medical device.
  • specific suitable medical devices include intracavitary devices such as a stent cover, a stent, a graft assembly, a ring, a suture and a prosthetic cardiac valve as well as extraluminal devices such as sheets, all such comprising leptin antagonist according to the teachings herein, EXAMPLE 18
  • a human subject is diagnosed with a peripheral or venous aneurysm, e.g., a visceral artery aneurysm, a cerebral aneurysm, especially a saccular or pseudo-fusiform aneurysm.
  • a peripheral or venous aneurysm e.g., a visceral artery aneurysm, a cerebral aneurysm, especially a saccular or pseudo-fusiform aneurysm.
  • a composition according to the teachings herein associated with a covered stent is provided, e.g., one or more of coating the stent, coating the stent cover, impregnating the stent, impregnating the stent cover, constituting the stent and constituting the stent cover.
  • the covered stent is deployed in the usual way, where the stent cover covers the mouth of the stent. Subsequently, leptin antagonist from the composition passes into and/or through the tissue in proximity to the aneurysm to provide a beneficial effect to the subject.
  • a composition according to the teachings herein is placed inside the cavity of the aneurysm through the mouth thereof, e.g., as a fluid composition (e.g., Example 6) or as an aneurysm coil that is impregnated with leptin antagonist, coated with leptin antagonist or is made of a composition according to the teachings herein.
  • a fluid composition e.g., Example 6
  • an aneurysm coil that is impregnated with leptin antagonist, coated with leptin antagonist or is made of a composition according to the teachings herein.
  • a person having ordinary skill in the art is able to implement coating an aneurysm coil with an active pharmaceutical ingredient with reference to, for example, Cerecyte® (Codman Neuro, a division of DePuySynthes, part of Johnson & Johnson, New Brunswick, NJ, USA), Nexus® (Micro Therapeutics, Inc., Irvine, CA, USA), and HydroCoil®, HydroSoft® (Terumo Corporation, Tokyo, Japan).
  • Cerecyte® Cosmetic Neuro, a division of DePuySynthes, part of Johnson & Johnson, New Brunswick, NJ, USA
  • Nexus® Micro Therapeutics, Inc., Irvine, CA, USA
  • HydroCoil®, HydroSoft® HydroSoft®

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Abstract

L'invention concerne des procédés, des compositions et des dispositifs comprenant un antagoniste de la leptine.
EP15883064.6A 2015-02-26 2015-08-27 Procédés et compositions relatifs à des antagonistes de la leptine Active EP3261582B1 (fr)

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IL253912B (en) 2022-02-01
US20160263292A1 (en) 2016-09-15
CA2977607A1 (fr) 2016-09-01
EP3261582B1 (fr) 2021-01-06
US20190117856A1 (en) 2019-04-25
WO2016135716A1 (fr) 2016-09-01
IL253912A0 (en) 2017-10-31
EP3261582A4 (fr) 2018-11-07

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